Caffeine Reduces 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells through the Adenosine A2B Receptor

Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11β-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11β-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine) were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1) both caffeine and paraxanthine decreased placental 11β-HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A2B receptor, since siRNA-mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11β-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11β-HSD2) abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11β-HSD2. Taken together, these findings reveal that placental 11β-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A2B receptor signaling in regulating placental 11β-HSD2, and consequently fetal development

Gene profiling of the erythro- and megakaryoblastic leukaemias induced by the Graffi murine retrovirus

<p>Abstract</p> <p>Background</p> <p>Acute erythro- and megakaryoblastic leukaemias are associated with very poor prognoses and the mechanism of blastic transformation is insufficiently elucidated. The murine Graffi leukaemia retrovirus induces erythro- and megakaryoblastic leukaemias when inoculated into NFS mice and represents a good model to study these leukaemias.</p> <p>Methods</p> <p>To expand our understanding of genes specific to these leukaemias, we compared gene expression profiles, measured by microarray and RT-PCR, of all leukaemia types induced by this virus.</p> <p>Results</p> <p>The transcriptome level changes, present between the different leukaemias, led to the identification of specific cancerous signatures. We reported numerous genes that may be potential oncogenes, may have a function related to erythropoiesis or megakaryopoiesis or have a poorly elucidated physiological role. The expression pattern of these genes has been further tested by RT-PCR in different samples, in a Friend erythroleukaemic model and in human leukaemic cell lines.</p> <p>We also screened the megakaryoblastic leukaemias for viral integrations and identified genes targeted by these integrations and potentially implicated in the onset of the disease.</p> <p>Conclusions</p> <p>Taken as a whole, the data obtained from this global gene profiling experiment have provided a detailed characterization of Graffi virus induced erythro- and megakaryoblastic leukaemias with many genes reported specific to the transcriptome of these leukaemias for the first time.</p

Access to Mutualistic Endosymbiotic Microbes: An Underappreciated Benefit of Group Living

The original publication is available at www.springerlink.com A central question in behavioral ecology has been why animals live in groups. Previous theories about the evolution of sociality focused on the potential benefits of decreased risk of predation, increased foraging or feeding efficiency, and mutual aid in defending resources and/or rearing offspring. This paper argues that access to mutualistic endosymbiotic microbes is an underappreciated benefit of group living and sets out to reinvigorate Troyer’s hypothesis that the need to obtain cellulolytic microbes from conspecifics influenced the evolution of social behavior in herbivores and to extend it to nonherbivores. This extension is necessary because the benefits of endosymbionts are not limited to nutrition; endosymbionts also help protect their hosts from pathogens. When hosts must obtain endosymbionts from conspecifics, they are forced to interact. Thus, complex forms of sociality may be more likely to evolve when hosts must repeatedly obtain endosymbionts from conspecifics than when endosymbionts can be obtained either directly from the environment, are vertically transmitted, or when repeated inoculations are not necessary. Observations from a variety of taxa are consistent with the ideas that individuals benefit from group living by gaining access to endosymbionts and the complexity of social behavior is associated with the mode of acquisition of endosymbionts. Ways to test this theory include (a) experiments designed to examine the effects of endosymbionts on host fitness and how endosymbionts are obtained and (b) using phylogenetic analyses to examine endosymbiont-host coevolution with the goal of determining the relationship between the mode of endosymbiont acquisition and host sociality